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Efficacy and Safety of Sirolimus in Active Systemic Lupus Erythematosus (SiroLupus)

Primary Purpose

Systemic Lupus Erythematosus

Status

Unknown status

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Sirolimus

Placebo

About this trial

This is an interventional treatment trial for Systemic Lupus Erythematosus focused on measuring mTOR, systemic lupus erythematosus, SLE, lupus erythematosus, sirolimus, rapamycin

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age between 18~65 years;
Fulfilling the 2012 SLICC criteria for SLE; time from SLE diagnosis ≥ 3 months;
Active disease as defined by a SLEDAI-2K score of ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia) at screening;
Serologically active defining as positive anti-dsDNA antibody (>10IU/ml) or hypocomplementemia (C3<0.90g/L)
Before the first dose of sirolimus, a stable regimen of oral corticoids (0-20 mg/day, prednisone or equivalent) ≥4 weeks; doses of antimalarials, or immunosuppressive agents (mycophenolate mofetil [MMF]/mycophenolic acid [MPA] ≤1.5g/day, or MTX ≤15mg/week) are required to be stable for at least 12 weeks prior to first dose). In addition, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, NSAIDs or other analgesics should be stable for at least 2 weeks.

Exclusion Criteria:

Concomitant connective tissue disease or inflammatory disease that might confound efficacy assessments, e.g., systemic sclerosis, rheumatoid arthritis, dermatomyositis/polymyositis, etc;
Neuropsychiatric SLE;
Severe active lupus nephritis (urinary protein ≥3.5g/24h or urine protein/creatine ration> 3500mg/g or eGFR < 60ml/1.73m2/min);
Pregnant or breast-feeding women;
Previous treatment with sirolimus or allergic to sirolimus;
Intravenous CTX within 6 months of enrollment;
Intravenous immunoglobulin or prednisone dose >100mg/day within 3 months;
Calcineurin inhibitors (e.g., tacrolimus or cyclosporin A) within 1 month;
Traditional Chinese Herb (such as Tripterygium wilfordii Hook F) within 1 month;
Concurrent active or uncontrolled infection (such as tuberculosis and hepatitis) requiring antibiotics or antivirus;
WBC count <3×10^9/L;
Abnormal biochemical indices including: alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.5 times upper limit of laboratory reference range; total bilirubin or blood lipid (including total cholesterol, triglycerides, and low-density lipoprotein) >2 times upper limit of laboratory reference range;
Subjects has certain conditions that may lead to dropping out of the study in advance or that may bring risk to subjects themselves if they participate in the study. This is judged by experienced clinicians.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sirolimus plus SOC

Placebo plus SOC

Arm Description

Sirolimus plus standard therapy (SOC) for SLE; Generic name: sirolimus (0.5mg capsule); Dosage: 1.5mg/day; Administration route: Oral

Placebo plus standard therapy (SOC) for SLE; Drug: Placebo comparator plus SOC; Administration route: Oral

Outcomes

Primary Outcome Measures

The Proportion of Patients Who Achieve an SLE Responder Index-4 (SRI-4) Composite Response at Week 24

SLE responder index-4 (SRI-4), is a composite outcome includes all of the following outcomes: a reduction of SLEDAI-2K ≥ 4 points, no new BILAG A organ domain scores and no more than 1 new BILAG B organ domain scores, and no worsening of PGA (increase < 0.3).

Secondary Outcome Measures

Change From Baseline in Complement Level at Week 24

Serum complement refers to C3 and C4, which are both detected in the central lab.

Change From Baseline in Titers of Anti-dsDNA Antibody at Week 24

Anti-dsDNA antibody is detected in the central lab using chemiluminiscence.

Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score at Week 24

The SLEDAI-2K is an established, validated SLE activity index. It is based on the presence of 24 features in 9 organ systems and measures disease activity in SLE patients in the previous 30 days. It is weighted according to the feature. Features are scored by the assessing physician if present within the last 30 days with more severe features having higher scores, and then simply added to determine the total SLEDAI 2K score, which ranges from 0 to 105, with higher scores representing increased disease activity.

Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24

PGA is recorded on a visual analogue scale (VAS; 0.0 to 10.0 centimeter [cm]). The scale for the physician's assessment ranges for 'no lupus activity' (0.0) to 'extremely active lupus' (10.0).

Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24

BICLA response defined as participants meeting following criteria: 1. BILAG improvement (all BILAG A scores at baseline improved to either B, C or D and all BILAG B scores at baseline improved to C or D and no worsening in disease activity defined as no new BILAG A scores and <= 1 new BILAG B score) and 2. no worsening of total SLEDAI-2K from baseline 3. < 1 cm increase in PGA and 4. no treatment failure criteria met. BILAG: assesses disease extent, severity (range: A [severe] to E [no disease]). SLEDAI-2K: assesses improvement in disease activity (range: 0 to 105; higher score = higher severity). PGA: assesses worsening in participant's general health status (0.0= 'no lupus activity' to 10.0 = 'extremely active lupus').

Full Information

NCT ID

NCT04582136

First Posted

October 3, 2020

Last Updated

October 3, 2020

Sponsor

Chinese SLE Treatment And Research Group

Collaborators

Beijing Municipal Science & Technology Commission, North China Pharmaceutical Group Corporation

1. Study Identification

Unique Protocol Identification Number

NCT04582136

Brief Title

Efficacy and Safety of Sirolimus in Active Systemic Lupus Erythematosus

Acronym

SiroLupus

Official Title

Efficacy and Safety of Sirolimus in Patients With Active Systemic Lupus Erythematosus Despite Standard of Care: a Multi-center, Double Blinded, Randomized, Placebo-controlled, Phase 2 Trial

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Unknown status

Study Start Date

November 2020 (Anticipated)

Primary Completion Date

November 2021 (Anticipated)

Study Completion Date

November 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Chinese SLE Treatment And Research Group

Collaborators

Beijing Municipal Science & Technology Commission, North China Pharmaceutical Group Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

5. Study Description

Brief Summary

This is a multi-center, double-blinded, randomized, placebo-controlled, phase 2 study to evaluate the efficacy and safety of sirolimus administered in addition to standard therapy, in patients with active SLE disease.

Detailed Description

This study is a multi-center, double-blinded, randomized, placebo-controlled, phase 2 clinical trial to assess the safety and efficacy of sirolimus in patients with active systemic lupus erythematosus despite receiving standard background therapy. Six large rheumatological referring centers across from China will participate in the study. The study is divided into two phases. The first phase is a 24-week randomized, double-blinded, placebo-controlled trial, from which the primary end point will be generated, and the second phase is a 24-week open-labeled extension trial. The study enrolls SLE patients between 18~65 years old who have SLEDAI-2K score ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia), despite conventional treatment (e.g., immunosuppressants, antimalarial drugs, glucocorticoids, NSAIDs, anti-hypertensive drugs, and/or topical medications). In addition, subjects must be serologically active (positive anti-dsDNA antibody and/or hypocomplementemia. Subjects will be randomly assigned by 1:1 ratio to receive sirolimus (1.5mg/day) or placebo for the first 24-week phase. In the second 24-week open-labeled phase, sirolimus patients receive the same dose of sirolimus, and placebo group are switched to receive sirolimus at 1.5mg/day

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Systemic Lupus Erythematosus

Keywords

mTOR, systemic lupus erythematosus, SLE, lupus erythematosus, sirolimus, rapamycin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

146 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sirolimus plus SOC

Arm Type

Experimental

Arm Description

Sirolimus plus standard therapy (SOC) for SLE; Generic name: sirolimus (0.5mg capsule); Dosage: 1.5mg/day; Administration route: Oral

Arm Title

Placebo plus SOC

Arm Type

Placebo Comparator

Arm Description

Placebo plus standard therapy (SOC) for SLE; Drug: Placebo comparator plus SOC; Administration route: Oral

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

rapamycin

Intervention Description

In the double-blinded phase, sirolimus 1.5mg/day plus SOC is administered throughout 24 weeks; in the open-label extension period, patients who opt to participate continue on sirolimus 1.5mg/day plus SOC for an additional 24 weeks.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

In the double-blinded phase, placebo plus SOC is administered throughout 24 weeks; in the open-label extension period, patients who opt to participate are switched to receive sirolimus 1.5mg/day plus SOC for an additional 24 weeks.

Primary Outcome Measure Information:

Title

The Proportion of Patients Who Achieve an SLE Responder Index-4 (SRI-4) Composite Response at Week 24

Description

Time Frame

24 weeks

Secondary Outcome Measure Information:

Title

Change From Baseline in Complement Level at Week 24

Description

Serum complement refers to C3 and C4, which are both detected in the central lab.

Time Frame

24 weeks

Title

Change From Baseline in Titers of Anti-dsDNA Antibody at Week 24

Description

Anti-dsDNA antibody is detected in the central lab using chemiluminiscence.

Time Frame

24 weeks

Title

Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score at Week 24

Description

Time Frame

24 weeks

Title

Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24

Description

PGA is recorded on a visual analogue scale (VAS; 0.0 to 10.0 centimeter [cm]). The scale for the physician's assessment ranges for 'no lupus activity' (0.0) to 'extremely active lupus' (10.0).

Time Frame

24 weeks

Title

Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24

Description

Time Frame

24 weeks

Other Pre-specified Outcome Measures:

Title

Change From Baseline in SLE Disease Activity Score (SLE-DAS) at Week 24

Description

SLE-DAS is a newly developed tools to assess SLE disease activity. It is a multinomial that includes 17 clinical or laboratory indices: arthritis, swollen joint count, mucocutaneous vasculitis, localized cutaneous rash, generalized cutaneous rash, alopecia, mucosal ulcers, hypocomplementaemia, increased anti-dsDNA antibody, proteinuria, thrombocytopenia, leucopenia, neuropsychiatric involvement, systemic vasculitis, cardiac/pulmonary involvement, myositis, serositis, and haemolytic anaemia.

Time Frame

24 weeks

Title

Percentage of Patients With Clinical Remission at week 24

Description

Clinical remission is defined as clinical SLEDAI-2K (cSLEDAI-2K, excluding items from hypocomplementemia or positive anti-dsDNA antibody) = 0 AND that allowable dose of glucocorticoids is ≤ 5 mg/day prednisone (or equivalent)

Time Frame

24 weeks

Title

Percentage of Patients With Lupus Low Disease Activity State (LLDAS) at week 24

Description

LLDAS is defined as: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0-3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents.

Time Frame

24 weeks

Title

Percentage of Patients With Hypocomplementemia returned to normal at week 24

Description

Percentage of patients whose hypocomplementemia are returned to normal (C3>0.90g/L AND C4>0.10g/L)

Time Frame

24 weeks

Title

Percentage of Patients With Anti-dsDNA Antibody decreased to negative at week 24

Description

Percentage of Patients With Anti-dsDNA Antibody decreased to <10 IU/ml.

Time Frame

24 weeks

Title

Change From Baseline in Urine Protein/Creatine Ratio (PCR) Among Patients With Baseline PCR >500mg/g at Week 24

Description

PCR is detected in the central lab

Time Frame

24 weeks

Title

The Time to First BILAG Flare

Description

First BILAG flare is defined as at least one new BILAG A score or at least two new BILAG B scores

Time Frame

24 weeks

Title

Proportions of Patients With an SRI-5 and SRI-6 Response at Week 24

Description

The definitions of SRI-5 and SRI-6 is similar with SRI-4 except for a reduction of SLEDAI-2K ≥ 5 points or ≥ 6 points respectively

Time Frame

24 weeks

Title

Proportion of Patients With No Worsening in BILAG at Week 24

Description

No worsening in BILAG is defined as no new BILAG A score and no more than one new BILAG B score

Time Frame

24 weeks

Title

Proportions of Patients With No Worsening in PGA at Week 24

Description

No increase in PGA scores

Time Frame

24 weeks

Title

Change From Baseline in 36-Item Short Form Survey (SF-36)

Description

As a concise health questionnaire, SF-36 comprehensively summarizes the quality of life of the subjects from eight aspects: physiological function, physiological function, physical pain, general health status, energy, social function, emotional function and mental health.

Time Frame

24 weeks

Title

Change From Baseline in Lupus Patient-Reported Outcome tool (LupusPRO)

Description

LupusPRO is a valid and reliable patient-reported health outcome targeting towards measuring health (HRQOL) and non-health related quality of life (Non HRQOL) among patients with systemic lupus erythematosus (SLE). It assess the quality of life from 14 aspects: lupus syptoms, cognition, lupus medications, procreation, physical health, sleep, vitality, pain, emotional health, body image, desires-goals, social-support, coping, satisfaction with care.

Time Frame

24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age between 18~65 years; Fulfilling the 2012 SLICC criteria for SLE; time from SLE diagnosis ≥ 3 months; Active disease as defined by a SLEDAI-2K score of ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia) at screening; Serologically active defining as positive anti-dsDNA antibody (>10IU/ml) or hypocomplementemia (C3<0.90g/L) Before the first dose of sirolimus, a stable regimen of oral corticoids (0-20 mg/day, prednisone or equivalent) ≥4 weeks; doses of antimalarials, or immunosuppressive agents (mycophenolate mofetil [MMF]/mycophenolic acid [MPA] ≤1.5g/day, or MTX ≤15mg/week) are required to be stable for at least 12 weeks prior to first dose). In addition, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, NSAIDs or other analgesics should be stable for at least 2 weeks. Exclusion Criteria: Concomitant connective tissue disease or inflammatory disease that might confound efficacy assessments, e.g., systemic sclerosis, rheumatoid arthritis, dermatomyositis/polymyositis, etc; Neuropsychiatric SLE; Severe active lupus nephritis (urinary protein ≥3.5g/24h or urine protein/creatine ration> 3500mg/g or eGFR < 60ml/1.73m2/min); Pregnant or breast-feeding women; Previous treatment with sirolimus or allergic to sirolimus; Intravenous CTX within 6 months of enrollment; Intravenous immunoglobulin or prednisone dose >100mg/day within 3 months; Calcineurin inhibitors (e.g., tacrolimus or cyclosporin A) within 1 month; Traditional Chinese Herb (such as Tripterygium wilfordii Hook F) within 1 month; Concurrent active or uncontrolled infection (such as tuberculosis and hepatitis) requiring antibiotics or antivirus; WBC count <3×10^9/L; Abnormal biochemical indices including: alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.5 times upper limit of laboratory reference range; total bilirubin or blood lipid (including total cholesterol, triglycerides, and low-density lipoprotein) >2 times upper limit of laboratory reference range; Subjects has certain conditions that may lead to dropping out of the study in advance or that may bring risk to subjects themselves if they participate in the study. This is judged by experienced clinicians.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Mengtao Li, MD

Phone

+86 13911788572

mengtao.li@cstar.org.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Liying Peng, MD

Phone

+86 15201435661

liying_penguin@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Xiaofeng Zeng, MD

Organizational Affiliation

Chinese SLE Treatment and Registration Group

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

all IPD that underlie results in a publication

IPD Sharing Time Frame

IPD will be available when the study result is published.

Learn more about this trial

Efficacy and Safety of Sirolimus in Active Systemic Lupus Erythematosus

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